Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
In vertebrates with a closed circulatory system, an elaborate mechanism involving cellular components as well as circulating plasma proteins has evolved to prevent significant blood loss following injury. The response to damage needs to be focused and commensurate with the extent of injury. In these schemes, coagulation proceeds through a series of proteolytic reactions involving enzymes that become activated, culminating in the generation of the final enzyme thrombin which activates platelets and cleaves a structural protein (fibrinogen) to generate a fibrin, providing a meshwork which physically prevents blood from leaving the vessel. Fibrin formation and platelet activation represent a major defense and repair mechanism, which ensures the integrity of vascular system. Deficiency of proteins that lead to the formation of thrombin can cause bleeding complications. One of the most common types of bleeding disorders is hemophilia A and B. Hemophilia A is characterized by a deficiency in coagulation factor VIII and hemophilia B is characterized by factor IX deficiency. Current therapy for hemophilia is carried out by replacement of the defective or missing coagulation factors. Unfortunately, some patients (˜3-20%) develop high-titer, inhibitory antibodies to the infused factor VIII or factor IX. Development of inhibitors against the administrated proteins represents a severe problem in the management of hemophilia. In these so-called inhibitor patients alternative strategies have been developed which bypass the intrinsic pathway such as activated prothrombin complex concentrates (aPCCs) and recombinant FVIIa (NovoSeven®). These products work by accelerating FXa formation and ultimately thrombin generation thereby providing adequate hemostasis. Because of a whole host of issues including short half-life, effective dose range, cost and potential for thrombotic complications other approaches should be explored. An alternative approach could be to infuse FXa directly; however it has a very short half-life in plasma and has the potential to activate multiple upstream pathways leading to a disseminated hemostatic response.